Plant-derived human butyrylcholinesterase, but not an organophosphorous-compound hydrolyzing variant thereof, protects rodents against nerve agents

The concept of using cholinesterase bioscavengers for prophylaxis against organophosphorous nerve agents and pesticides has progressed from the bench to clinical trial. However, the supply of the native human proteins is either limited (e.g., plasma-derived butyrylcholinesterase and erythrocytic ace...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 107; no. 47; pp. 20251 - 20256
Main Authors Geyer, Brian C., Kannan, Latha, Garnaud, Pierre-Emmanuel, Broomfield, Clarence A., Cadieux, C. Linn, Cherni, Irene, Hodgins, Sean M., Kasten, Shane A., Kelley, Karli, Kilbourne, Jacquelyn, Oliver, Zeke P., Otto, Tamara C., Puffenberger, Ian, Reeves, Tony E., Robbins, Neil, Woods, Ryan R., Soreq, Hermona, Lenz, David E., Cerasoli, Douglas M., Mor, Tsafrir S., Arntzen, Charles J.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 23.11.2010
National Acad Sciences
Subjects
Acetylcholinesterase
Animals
Biological Sciences
Butyrylcholinesterase - metabolism
Butyrylcholinesterase - pharmacokinetics
Butyrylcholinesterase - pharmacology
Chemical Warfare Agents - metabolism
Chemical Warfare Agents - toxicity
Cholinesterase
Chromatography, High Pressure Liquid
Clinical trials
Disease control
Dosage
Drug interactions
Enzymes
Flowers & plants
Guinea Pigs
Humans
hydrolase
Immunoblotting
Kinetics
Mice
Morbidity
Mortality
nerve agents
Nerves
Neuroprotective Agents - metabolism
Neuroprotective Agents - pharmacokinetics
Neuroprotective Agents - pharmacology
Nicotiana - metabolism
organophosphorus acid anhydride
Organophosphorus Compounds - metabolism
Organophosphorus Compounds - toxicity
Oximes
Pain
Pesticides
Pesticides - metabolism
Pesticides - toxicity
Pharmacokinetics
Phosphorus
Plants
Poisoning
Polyethylene glycol
Polyethylene Glycols - metabolism
Prophylaxis
Protein Engineering
Proteins
Rodents
Toxicity
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Summary:The concept of using cholinesterase bioscavengers for prophylaxis against organophosphorous nerve agents and pesticides has progressed from the bench to clinical trial. However, the supply of the native human proteins is either limited (e.g., plasma-derived butyrylcholinesterase and erythrocytic acetylcholinesterase) or nonexisting (synaptic acetylcholinesterase). Here we identify a unique form of recombinant human butyrylcholinesterase that mimics the native enzyme assembly into tetramers; this form provides extended effective pharmacokinetics that is significantly enhanced by polyethylene glycol conjugation. We further demonstrate that this enzyme (but not a G117H/E197Q organophosphorus acid anhydride hydrolase catalytic variant) can prevent morbidity and mortality associated with organophosphorous nerve agent and pesticide exposure of animal subjects of two model species.
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Author contributions: B.C.G., D.E.L., D.M.C., and T.S.M. designed research; B.C.G., L.K., P.-E.G., C.L.C., I.C., S.M.H., S.A.K., K.K., J.K., Z.P.O., T.C.O., I.P., T.E.R., N.R., and R.R.W. performed research; B.C.G., L.K., C.A.B., H.S., D.E.L., D.M.C., and T.S.M. analyzed data; and B.C.G., L.K., H.S., D.E.L., D.M.C., and T.S.M. wrote the paper.
2Present address: University of Arizona College of Medicine, 550 East Van Buren Street, Phoenix, AZ 85004.
3Present address: Cancer and Cell Biology Division, Translational Genomics Research Institute, 445 North Fifth Street, Phoenix, AZ 85004.
1B.C.G. and L.K. contributed equally to this work.
Edited* by Charles J. Arntzen, Arizona State University, Tempe, AZ, and approved October 6, 2010 (received for review June 23, 2010)
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1009021107